High drug load formulations and dosage forms

Abstract

The invention relates to high drug load formulations containing (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient.

1 . A unit dosage form comprising from 55-90% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 10-45% by weight excipient, wherein said unit dosage form has 200 mg or more of (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       2 . The unit dosage form of  claim 1  having from 200-800 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       3 . The unit dosage form of  claim 1  having from 300-500 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       4 . The unit dosage form of  claim 3  wherein the total weight of said dosage form is no more than 800 mg.  
   
   
       5 . The unit dosage form of  claim 3  wherein the total weight of said dosage form is no more than 700 mg.  
   
   
       6 . The unit dosage form of  claim 1  wherein said excipient comprises microcrystalline cellulose.  
   
   
       7 . The unit dosage form of  claim 1  wherein said (R)-2-(2-fluoro-4-biphenylyl)propionic acid is the free acid form of (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       8 . The unit dosage form of  claim 1  wherein said dosage form is a tablet or a capsule.  
   
   
       9 . The unit dosage form of  claim 1  wherein said dosage form is a tablet.  
   
   
       10 . A unit dosage form comprising from 380-420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid and from 200-260 mg excipient.  
   
   
       11 . A unit dosage form comprising from 200-600 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid that is more than 55% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       12 . The unit dosage form of  claim 11  having from 350-450 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid and less than 300 mg excipient.  
   
   
       13 . The unit dosage form of  claim 12  wherein when orally administered to a fasting subject provides a C max  of from about 30 to about 95 μg/ml.  
   
   
       14 . The unit dosage form of  claim 13  which is suitable for oral administration.  
   
   
       15 . The unit dosage form of  claim 14  which is a tablet or a capsule.  
   
   
       16 . The unit dosage form of  claim 15  which is a tablet.  
   
   
       17 . A unit dosage form comprising from 55-80% by weight (R)-2-(2-fluoro-4-biphenylyl)propionic acid and from about 20-45% by weight excipient that has a total weight of less than 800 mg.  
   
   
       18 . The unit dosage form of  claim 17 , having from 380-420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid.  
   
   
       19 . The unit dosage form of  claim 17 , wherein said excipient comprises microcrystalline cellulose.  
   
   
       20 . The unit dosage form of  claim 19  further comprising hydroxypropyl methylcellulose.  
   
   
       21 . The unit dosage form of  claim 17  further comprising lactose, colloidal silicon dioxide, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate.  
   
   
       22 . The unit dosage form of  claim 21  which is a coated tablet.  
   
   
       23 . The unit dosage form of  claim 21  having from about 380 mg to 420 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 50 mg to 70 mg lactose, from about 3 mg to 7 mg colloidal silicon dioxide, from about 30 mg to 50 mg hydroxypropyl methylcellulose, from about 70 mg to 105 mg microcrystalline cellulose, from about 1 mg to 5 mg croscarmellose sodium, from about 4 mg to 8 mg magnesium stearate, and optional ingredients as desired.  
   
   
       24 . The unit dosage form of  claim 21  having from about 385 mg to 415 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 55 mg to 65 mg lactose, from about 3.5 mg to 6.5 mg colloidal silicon dioxide, from about 32 mg to 48 mg hydroxypropyl methylcellulose, from about 75 mg to 100 mg microcrystalline cellulose, from about 1.5 mg to 4.5 mg croscarmellose sodium, from about 4.5 mg to 7.5 mg magnesium stearate, and optional ingredients as desired.  
   
   
       25 . The unit dosage form of  claim 21  having from about 390 mg to 410 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 56 mg to 64 mg lactose, from about 4.0 mg to 6.5 mg colloidal silicon dioxide, from about 34 mg to 46 mg hydroxypropyl methylcellulose, from about 80 mg to 95 mg microcrystalline cellulose, from about 2.0 mg to 4.0 mg croscarmellose sodium, from about 5.0 mg to 7.0 mg magnesium stearate, and optional ingredients as desired.  
   
   
       26 . The unit dosage form of  claim 21  having from about 395 mg to 405 mg (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from about 56 mg to 64 mg lactose, from about 4.0 mg to 6.0 mg colloidal silicon dioxide, from about 34 mg to 46 mg hydroxypropyl methylcellulose, from about 82 mg to 93 mg microcrystalline cellulose, from about 2.0 mg to 4.0 mg croscarmellose sodium, from about 5.0 mg to 7.0 mg magnesium stearate, and optional ingredients as desired.  
   
   
       27 . A method of manufacturing a tablet unit dosage form having (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient comprising: 
 (a) charging the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, and colloidal silicon dioxide into a drum-type blender;    (b) blending components together for a sufficient amount of time and discharge into a mill;    (c) milling through a sufficient size screen to decrease the particle size of the large particles in the drug substance and discharging into a high shear granulator;    (d) charging the hydroxypropyl methylcellulose into the high shear granulator and dry blending;    (e) granulating the material using purified water;    (f) milling the wet granulation through an appropriate size screen;    (g) drying the milled granulation;    (h) milling the dried granulation through an appropriate size screen;    (i) charging dried granulation along with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide into a diffusion blender and blending the material for an appropriate amount of time;    (j) charging the magnesium stearate into the diffusion blender and blending for an appropriate amount of time;    (k) compressing the blended powders on a high-speed rotary press; and    (l) film coating the tablets.    
   
   
       28 . A composition having (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, and one or more glidants as ingredients.  
   
   
       29 . The composition of  claim 28  having 50-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid; 1-30% of the total weight as one or more diluents present; and 0.01-5% of the total weight as one or more glidants.  
   
   
       30 . The composition of  claim 28  having 60-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid; 3-25% of the total weight as one or more diluents present; and 0.1-5% of the total weight as one or more glidants.  
   
   
       31 . The composition of  claim 28  having 70-95% of the total weight as (R)-2-(2-fluoro-4-biphenylyl)propionic acid; 5-20% of the total weight as one or more diluents present; and 0.1-3% of the total weight as one or more glidants.  
   
   
       32 . A composition having (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, one or more glidants, one or more binders, one or more wetting agents and optionally, one or more additional ingredients.  
   
   
       33 . A composition having from 40-95% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 1-30% of one or more diluents, from 0.01-10% of one or more glidants, from 1-30% of one or more binders, from 1-40% of one or more wetting agents and from 0-20% of one or more optional ingredients.  
   
   
       34 . A composition having from 45-95% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 1-20% one or more diluents, from 0.01-5% of one or more glidants, from 1-20% of one or more binders, from 1-25% of one or more wetting agents and from 1-20% of one or more optional ingredients.  
   
   
       35 . A composition having from 50-90% (R)-2-(2-fluoro-4-biphenylyl)propionic acid, from 5-15% of one or more diluents, from 0.1-5% of one or more glidants, from 1-15% of one or more binders, from 5-25% of one or more wetting agents and from 1-10% of one or more optional ingredients.  
   
   
       36 . A composition having a dried granulation component and one or more disintegrants wherein the dried granulation has (R)-2-(2-fluoro-4-biphenylyl)propionic acid, one or more diluents, one or more binders, and one or more glidants.  
   
   
       37 . The composition of  claim 36  wherein the one or more disintegrants is 1-40% of the total weight of the composition.  
   
   
       38 . The composition of  claim 36  wherein the one or more disintegrants is 5-25% of the total weight of the composition.  
   
   
       39 . The composition of  claim 36  wherein the one or more disintegrants is 5-20% of the total weight of the composition.  
   
   
       40 . A method of using the unit dosage form of  claim 1  comprising identifying and individual in need of treatment and administering to said individual a therapeutically effective amount the unit dosage form of  claim 1 .  
   
   
       41 . The method of  claim 40  wherein said individual in need of treatment has a neurodegenerative disorder.  
   
   
       42 . The method of  claim 41  wherein said neurodegenerative disorder is chosen from Alzheimer's disease, dementia, mild cognitive impairment, Parkinson's disease, Huntington's disease and symptoms thereof  
   
   
       43 . The method of  claim 42  wherein said Alzheimer's disease is chosen from prodromal Alzheimer's disease, mild Alzheimer's disease, mild-to-moderate Alzheimer's disease, moderate Alzheimer's disease, moderate-to-severe Alzheimer's disease, and severe Alzheimer's disease.  
   
   
       44 . The method of  claim 42  wherein said Alzheimer's disease is mild Alzheimer's disease.  
   
   
       45 . The method of  claim 41  wherein said unit dosage form is administered twice daily.  
   
   
       46 . The method of  claim 41  wherein said unit dosage form comprises from about 320 to 480 mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid or molar equivalent of a pharmaceutically acceptable salt thereof and said individual is administered two unit dosage forms twice daily.  
   
   
       47 . The method of  claim 46  wherein said individual has Alzheimer's disease or is desiring prophylaxis against the development of symptoms of Alzheimer's disease.  
   
   
       48 . The method of  claim 40  wherein said individual in need of treatment has cancer.  
   
   
       49 . The method of  claim 48  where in said cancer is chosen from brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cell, colon, stomach, breast, endometrial, prostate, testicle, ovary, skin, and head and neck, esophagus, and bone marrow cancer.  
   
   
       50 . The method of  claim 48  wherein said cancer is prostate cancer.  
   
   
       51 . A method of manufacturing a tablet unit dosage form having (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient comprising: 
 (a) charging the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, colloidal silicon dioxide, and hydroxypropyl methylcellulose into the high shear granulator;    (b) dry blending the lactose, (R)-2-(2-fluoro-4-biphenylyl)propionic acid drug substance, colloidal silicon dioxide, and hydroxypropyl methylcellulose in the high shear granulator;    (c) granulating the material using purified water;    (d) milling the wet granulation through an appropriate size screen;    (e) drying the milled granulation;    (f) milling the dried granulation through an appropriate size screen;    (g) charging dried granulation along with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide into a diffusion blender and blending the material for an appropriate amount of time;    (h) charging the magnesium stearate into the diffusion blender and blending for an appropriate amount of time;    (i) compressing the blended powders on a high-speed rotary press; and    (j) film coating the tablets.